This invention relates to the treatment of neuropathy resulting from ischemic reperfusion injury in a mammal. Such neuropathies include, but are not limited to, optic ischemic neuropathy, stroke, reperfusion injury after TPA treatment or other lytic treatments/carotid endarterectomy, seizures, and excitotoxic retinal damage in glaucoma.
When the blood supply to neural tissues such as brain or retina is interrupted, a complex series of biochemical changes begins which may result in neuronal cell damage. At the cellular level, it is known in the art that damage is mediated by opening of the N-methyl-D-aspartate channels in the membrane. Ischemia begins when the blood supply stops or is significantly slowed, and this phase may be followed by restoration of the blood supply during a reperfusion phase. It is well established that cellular damage may occur during both phases, though by different mechanisms. These processes and the mechanisms for damage are described in xe2x80x9cClinical Challenges. Retinal Artery Occlusionxe2x80x9d H. S. Mangat, Survey of Ophthalmology 40, 145-156 (1995), which is incorporated in its entirety by reference herein.
The complex series of events known in the art to contribute to cell death during ischemia/reperfusion are summarized in FIG. 1 in diagrammatic form. FIG. 1 shows six substances that accumulate during ischemia: excitatory amino acids (1), intracellular calcium (2), arachidonic and other free fatty acids (3), hypoxanthine (4), xanthine oxidase (5), and platelet activating factor (6).
Ischemia triggers at least three pathways deleterious to the cell. Firstly, a lack of oxygen depletes energy stores (principally ATP), which disrupts homeostatic mechanisms, most importantly the membrane pump mechanism that maintains intracellular calcium at a low level. The resulting rise in intracellular calcium (2), which occurs principally because of the opening of the N-methyl-D-aspartate (NMDA) channels in the membrane, increases release of glutamic acid, activates destructive proteases and lipases (7), and indirectly converts the enzyme xanthine dehydrogenase (8) to the potentially harmful xanthine oxidase (5). Secondly, excitatory amino acids (1) (xe2x80x9cexcitotoxinsxe2x80x9d), principally glutamic and aspartic acids, are released, which activate calcium channels, further increasing intracellular calcium through a positive feedback mechanism, and allowing entry into the cell of excess water, sodium and chloride. Thirdly, acidosis enhances destructive lipid peroxidation and the release of damaging free radicals (9).
Upon restoration of the blood supply the reperfusion phase begins. The increased intracellular calcium level (2), a result of opened NMDA channels during ischemia, may now trigger a more destructive cascade. The initial calcium impulse causes a cascade that results in the release of intracellular calcium stores from the intravesicular calcium deposit. The release of intracellular calcium is mediated via the ryanodine receptor, principally the type 3 ryanodine receptor. The net result is a thirtyfold rise in intracellular calcium and cell death. Attempts have been made to reperfuse as soon as possible after the onset of ischemia, but it is important to note that the reperfusion itself causes the cascade, therefore the neurodestructive phases of ischemia and reperfusion are distinct.
Neurophysiologists now view reperfusion injury as a cascade process that leads to excitotoxic cell death. The rise in intracellular calcium during reperfusion causes vasoconstriction of neighboring blood vessels. In addition, it causes the release of free oxygen radicals (9), in part from the action of xanthine oxidase (5). The net result is excitotoxic neuronal cell death (10).
Ryanodine Receptor Antagonists
Increased cytosolic Ca2+ concentration contributes significantly to neuronal cell damage during ischemic reperfusion. It is desirable to prevent or minimize ischemic neuronal reperfusion injury; that is, to prevent or minimize neuronal cell damage that occurs during the reperfusion phase of an ischemic episode.
Dantrolene is an antagonist of the type 3 ryanodine receptor and is commonly given as the sodium salt (sodium dantrium), which is hydrated 1-[[[5-(4-nitrophenyl)2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt. Dantrolene is prescribed in the treatment of clinical spasticity resulting from upper motor neuron disorders such as spinal chord injury, cerebral palsy, stroke, or multiple sclerosis. Dantrolene is also effective in reversing the hypermetabolic process of malignant hyperthermia, a genetic disorder of skeletal muscle that is triggered by exposure to anesthetics and certain relaxants.
Other therapeutic uses for dantrolene are known in the art. For example, Dreyer, U.S. Pat. No. 5,597,809, teaches the use of NMDA-receptor antagonists, and also dantrolene, for the treatment of optic neuritis. U.S. Pat. No. 5,506,231 to Lipton teaches the use of dantrolene for the treatment of three conditions specifically associated with AIDS: dementia, myelopathy, and blindness. Dantrolene has been used clinically to treat malignant hypothermia, as it is known to reduce cellular energy requirements, creating a hypothermic environment. Kiyoshi (Patent Abstracts of Japan (1994), publication number 06263636) discloses the use of dantrolene for treatment of cerebral nerve diseases such as geriatric dementia, Parkinsons disease and Huntingtons disease.
Non-therapeutic uses for dantrolene include cryopreservation of blood vessels. See U.S. Pat. Nos. 5,158,867; 5,149,621; 5,145,769 and 5,122,110.
Ischemic Optic Neuropathy
Ischemic optic neuropathy (ION) is a distinct condition from optic neuritis (ON), and ION is distinguished from ON by several diagnostic criteria. Typically, ION patients are 60 years or older, while ON affects younger patients for whom 40 years is the typical age of onset. A key event in the development of ION pathology is ischemia, whereas inflammation is essential to the pathology of ON. In the majority of cases, ION is a painless condition. In contrast, ON is reported to be very painful. Finally, and most significantly to the present invention, the visual acuity lost by a patient having ON is recovered in the majority (71%) of cases. In contrast, for the vast majority of ION patients, loss of visual acuity is permanent and spontaneous recovery is very rare. See American Academy of Ophthalmology (1994) pp.76-83. It is therefore desirable to prevent or minimize the loss of visual acuity.